The present application is related to U.S. Ser. No. 08/059,038, filed May 7, 1993(now U.S. Pat. No. 5,413,999) and U.S. Ser. No. 08/212,603 (now U.S. Pat. No. 5,420,353.
The present invention is concerned with a novel intermediate and process for synthesizing compounds which inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular certain oligopeptide analogs, such as compound J of the Examples below. These compounds are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). These compounds are also useful for inhibiting renin and other proteases.
The invention described herein concerns a process to effect the regiospecific generation of a cis-1-amino-2-alklanol, particularly cis-1-amino-2-indanol (Compounds C and F) from either a 1,2 -diol precursor or from a 2-halo-1-alkanol. For 1,2-diol precursors, the stereochemical integrity of the carbon-oxygen bond at position 2 of the indan core is retained, so that there is substantially complete conversion to the appropriate product 1-amino-2-indanol. For example, 1R,2S-indandiol and 1S,2S-indandiol (Compounds A and B) each produce substantially 1R-amino-2S-indanol (Compound C). Similarly, 1R,2R-indandiol and 1S,2R indandiol each produce substantially 1S,2R-indandiol. Mixtures of enantiomeric diol precursors produce substantially the same mixture of 1-amino-2-alkanol enantiomers.
For 2-halo-1-indanol precursors, the stereochemistry of the carbon at position 2 of the indane core is inverted so that there is substantially complete conversion to the appropriate product cis-1-amino-2-indanol. For example, 2S-bromo-1S-indanol (compound G) produces substantially 1S-amino-2R-indanol (Compound F), and 2R-bromo-1R-indanol (compound H) produces substantially 1R-amino-2S-indanol (Compound C). Mixtures of enantiomeric 2-halo-1-alkanol precursors produce substantially the same mixture of 1-amino-2-alkanol enantiomers. ##STR1##
The process described is superior to prior an in that the process is shorter, more productive, higher yielding and has less environmental impact.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988) demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. The end product compounds, including certain oligopeptide analogs that can be made from the novel intermediates and processes of this invention are inhibitors of HIV protease, and are disclosed in EPO 541,168, which published on May 12, 1993. See, for example, compound J therein.
Previously, the synthesis of compound J and related compounds was accomplished via a 12-step procedure. This procedure is described in EPO 541,168. The extreme length of this route (12 steps), renders this process time consuming and labor intensive, and it requires the use of many presently expensive reagents and a presently expensive starting material. A route requiting fewer reaction steps and reagents would provide desirable economical and time-saving benefits.
In the case of the diol precursor, this invention provides a process for the regiospecific synthesis of cis-1-amino-2-indanol from 1,2-indane diol, with specific retention of the stereochemical integrity of the carbon at the 2 position. The indane diol is treated with a strong acid, then hydrolyzed with water to give the target compound. This process of the present invention is a one step procedure, and avoids isolation of any intermediate.
For the 2-halo-1-indanol precursor, this invention provides a process for the regiospecific synthesis of cis-1-amino-2-indanol, with the specific inversion of the stereochemistry of the carbon at the 2 position. The 2-halo-1-indanol is treated with strong acid to give a 1-acetamido-2-halo intermediate, then base is added to form an oxazoline intermediate. Treatment with aqueous weak acid gives the desired product.
The preparation of 1-amino-2-indanol was previously accomplished via a multistep sequence. This sequence involved the treatment of an indene oxide with aqueous ammonia to produce a trans 1-amino-2-indanol (Cpd J). ##STR2## The intermediate J was then treated with an acyl halide, thereby convening the amine to an amide intermediate (Cpd K). The hydroxyl group of the hydroxy amide K is activated by conversion to an mesylate (Cpd L), then induced to cyclize and form the oxazoline M. The oxazoline B produced by this prior art method is purified, then subjected to conditions similar to that described above effecting its conversion to the target cis-1-amino-1-indanol.
The application of 1,2 diols in the Ritter reaction is novel. See, for example, L. I. Krimen et al., Organic Reactions Vol. 17 John Wiley & Sons New York 1969 (covers up to 1966); R. Bishop, Comprehensive Organic Synthesis eds. B. M. Trost et al., Pergammon Press New York, 1991 vol. 6. Glycols are well known when the two alcohol functions are separated by more than one carbon atom. They react as individual alcohols or assist in forming a larger ting. Based on known chemistry in the literature, one would expect a 1,2 diol in strong acid to undergo a pinacol rearrangement to lose a mole of water and form 2-indanone, as pictured as follows. ##STR3##
The process of the present invention provides a route with fewer chemical steps to accomplish the same overall synthesis of cis-1-amino-2-indanol. Furthermore, the isolation of intermediates is not necessary in the present invention. Also, the present process utilizes smaller quantities of organic solvents and proceeds in greater overall yield than prior methods, a result providing lower environmental impact than prior methods.